| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
IC50: 15 nM (Aβ40)[1].
Begacestat targets gamma-secretase, an enzyme complex involved in the cleavage of amyloid precursor protein (APP) to produce amyloid-β peptides. It selectively inhibits APP cleavage over Notch cleavage. It lowers levels of Aβ42 and Aβ40 with EC50 values of 12.4 and 14.8 nM, respectively, in cells expressing human recombinant APP. |
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| ln Vitro |
In vitro, begacestat inhibits gamma-secretase with an IC50 of 15 nM for Aβ40 production. It lowers levels of Aβ42 and Aβ40 with EC50 values of 12.4 and 14.8 nM, respectively, in cells expressing human recombinant APP. It selectively inhibits APP cleavage over Notch cleavage.
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| ln Vivo |
Aβ40 and Aβ42 in the brain are dramatically reduced after 4 hours of benacestat (5 mg/kg, po in mice) administration (37% lowering of brain Aβ40 and 25% lowering of Aβ40 observed)[1]. When taken orally three hours prior to training, benacestat (GSI-953: 0, 2.5, 5, or 10 mg/kg, oral gavage, three hours) causes a dose-dependent reversal of contextual fear conditioning deficits. When compared to vehicle-dosed Tg2576 mice, significant impairments are seen following treatment with 2.5 mg/kg Begacestat, with partial reversal at 5 mg/kg and complete reversal at 10 mg/kg[2]. Males at all dosages show a slightly lower percentage of SP CD4+ cells (SP CD4+ cells=~11% in controls compared with ~7% to ~9% in animals dosed with Begacestat), while females at 2000 mg/kg/day show a slightly lower percentage of SP CD4+ cells (SP CD4+ cells=~10% in controls compared with ~8% in animals dosed with Begacestat)[2].
In vivo, begacestat dramatically reduces brain Aβ40 and Aβ42 levels after oral administration in mice. At 5 mg/kg, it lowers brain Aβ40 by 37% and Aβ42 by 25% after 4 hours. It has been studied as a potential therapeutic agent for Alzheimer's disease and other neurodegenerative disorders. |
| Enzyme Assay |
In vitro enzyme assays for begacestat typically involve measuring the inhibition of gamma-secretase activity using cell-free or cell-based systems. Membrane preparations containing gamma-secretase are incubated with a substrate (e.g., APP-derived peptide) and varying concentrations of the compound. Aβ production is measured by ELISA or mass spectrometry. IC50 values are calculated from dose-response curves.
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| Cell Assay |
Cell-based assays for begacestat involve culturing cells expressing human recombinant APP in appropriate media. Cells are treated with begacestat at concentrations ranging from 0.1 nM to 10 µM for 4-24 hours. Aβ40 and Aβ42 levels in the culture medium are measured by ELISA. Notch signaling is assessed to evaluate selectivity. Cytotoxicity is assessed by standard viability assays.
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| Animal Protocol |
Animal/Disease Models: Tg2576 mice[2]
Doses: 0, 2.5, 5, or 10 mg/kg Route of Administration: po (oral gavage) for two days Experimental Results: Resulted in a dose-dependent reversal of contextual fear conditioning deficits when compound is orally administered 3 h before training. Animal/Disease Models: SD (Sprague-Dawley) rats[2] Doses: 0, 200, 600, or 2000 mg/kg/day for 10 (5 males/group and 5 females at Route of Administration: PO for 10 (5 males/group and 5 females at 600 mg/kg/day) or 28 (10/sex/group) days . Experimental Results: A dosage-related trend of slightly lower percentages of SP CD4+ cells in males at all dosages and females at 2000 mg/kg/day was observed. In vivo animal experiments for begacestat typically involve administration to transgenic mouse models of Alzheimer's disease (e.g., APP/PS1 mice) via oral gavage. Brain Aβ levels are measured by ELISA or immunohistochemistry. Cognitive function is assessed by behavioral tests. Pharmacokinetic parameters are evaluated by measuring compound levels in blood and brain. Toxicity is assessed by monitoring body weight and organ histology. |
| ADME/Pharmacokinetics |
Begacestat (molecular weight ~350, formula C9H8ClF6NO3S2) is orally active. It is metabolized in the liver and excreted via bile and urine. It penetrates the blood-brain barrier to reach its target in the brain. Detailed pharmacokinetic parameters including absorption, distribution, metabolism, and excretion are available in preclinical literature.
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| Toxicity/Toxicokinetics |
No detailed toxicology data are specifically available for begacestat from the search results. As a gamma-secretase inhibitor, potential toxicity may include effects on Notch signaling, which is involved in cell differentiation and development. Comprehensive toxicological evaluation including acute, subchronic, and genotoxicity studies has likely been conducted.
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| References |
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| Additional Infomation |
Begacestat has been used in trials investigating Alzheimer's disease treatment and basic science.
Begacestat (GSI953) (CAS#: 769169-27-9) is a selective γ-secretase inhibitor. It reduces Aβ production by inhibiting APP cleavage. It selectively inhibits APP over Notch cleavage. It has been studied for Alzheimer's disease. IC50 Aβ40 = 15 nM. Formula: C9H8ClF6NO3S2. |
| Molecular Formula |
C9H8CLF6NO3S2
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|---|---|
| Molecular Weight |
391.7274
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| Exact Mass |
390.954
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| Elemental Analysis |
C, 27.60; H, 2.06; Cl, 9.05; F, 29.10; N, 3.58; O, 12.25; S, 16.37
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| CAS # |
769169-27-9
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| PubChem CID |
11269353
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| Appearance |
White to off-white solid powder
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| LogP |
4.253
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
22
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| Complexity |
463
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=C(SC(=C1)Cl)S(=O)(=O)N[C@H](CO)C(C(F)(F)F)C(F)(F)F
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| InChi Key |
PSXOKXJMVRSARX-SCSAIBSYSA-N
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| InChi Code |
InChI=1S/C9H8ClF6NO3S2/c10-5-1-2-6(21-5)22(19,20)17-4(3-18)7(8(11,12)13)9(14,15)16/h1-2,4,7,17-18H,3H2/t4-/m1/s1
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| Chemical Name |
5-Chloro-N-((1S)-3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl)thiophene-2-sulfonamide
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| Synonyms |
GSI953; Begacestat; 769169-27-9; 5-chloro-N-[(2S)-4,4,4-trifluoro-1-hydroxy-3-(trifluoromethyl)butan-2-yl]thiophene-2-sulfonamide; 3666C56BBU; Begacestat; GSI-953; GSI 953
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~127.64 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5528 mL | 12.7639 mL | 25.5278 mL | |
| 5 mM | 0.5106 mL | 2.5528 mL | 5.1056 mL | |
| 10 mM | 0.2553 mL | 1.2764 mL | 2.5528 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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